The proposed research project involves the study of the molecular and cellular mechanism of epilepsy. Epilepsy is a family of neurological disorders characterized by the unpredictable but recurrent occurrence of seizures, which are uncontrolled sudden attacks triggered by unusually intense neuronal firing. The model system that will be used in this proposed project is a murine model of status epilepticus (SE). In our SE model, systemically administered pilocarpine induces prolonged SE which results in hyperexcitability in the hippocampus and selective neuronal degeneration as observed in human epilepsy. Seizures also rapidly induce the expression of the multifunctional neuronal modulator, cyclooxygenase-2 (COX2), in principle neurons of the hippocampus. Our preliminary data demonstrate that pharmacologic inhibition of COX2, when initiated after SE, largely prevents the loss of synaptic inhibition onto dentate granule cells, suggesting that a signaling pathway critically involving COX2 mediates loss of GABAergic inhibition after SE. My first objective in this project is to test two alternative hypotheses that could explain the COX2-mediated loss of inhibition of granule neurons after SE. First, the possibility of COX2 mediating degeneration of somatostatin labeled GABAergic interneurons in CA1 area and dentate hilus and/or second the enhanced frequency dependent presynaptic inhibition of granule cell afferents to the dentate interneuron population after SE. To test both hypotheses we will compare the number of injured neurons within the CA1 pyramidal cell layer and dentate hilar interneurons using an immunohistochemical approach, in addition to measuring intrinsic synaptic properties of the dentate interneurons and granule cells using an electrophysiological approach. As a second objective I will determine whether the principle neurons of the hippocampus are the source of COX2 involved in loss of inhibition after SE, exploring the beneficial effects of blocking neuronal and nonneuronal COX2 induction after seizure using both a pharmacological and a genetic approach. At the end of the proposed project we will be able to understand the role of COX2 induction and its signaling pathways in the synaptic plasticity observed in the hippocampal network after SE. These experiments should provide us with new information regarding inhibitory synaptic plasticity modulation in the normal and epileptic hippocampus. As an advantage, the pharmacology of COX2 and its downstream signaling are well studied and understood. Demonstrating that SE-induced COX2 signaling is involved in the synaptic plasticity and/or selective neurodegeneration that occurs in the hippocampus after SE could lead to a strategy for interrupting epileptogenesis and be used as an efficacious therapeutic treatment for epilepsy prevention and impact the lives of those with this neurological disorder.